Acetylated(1-adamantyloxy) alkylamine compounds



United States Patent 3,539,630 ACETYLATED(1-ADAMANTYLOXY) ALKYL- AMINECOMPOUNDS Stephen Slomo Szinai, Wokingham, and Jiban Kumar Chakrabarti,Frimley, England, assignors to Eli Lilly and Company, Indianapolis,Ind., a corporation of Indiana No Drawing. Filed July 11, 1968, Ser. No.743,941 Claims priority, application Great Britain, July 18, 1967,32,914/ 67 Int. Cl. C07c 103/38 US. Cl. 260561 4 Claims ABSTRACT OF THEDISCLOSURE Acetylated (1-adamantyloxy)alkylamine compounds useful asdepressants for the central nervous system.

BACKGROUND OF THE INVENTION South African Pat. 65/4,102, issued toGeigy, A. G., discloses certain adamantylguanidine compounds of thewherein A represents methylene or ethylene; X represents oxygen, sulfur,imino, or lower alkylimino; and R R and R represent a hydrogen atom orat most two of these three symbols represent lower alkyl radicals. Theseadamantylguanidine compounds have sympathicolytic activities which aretherapeutically useful for the treatment of hypertension; they also haveantiviral activity.

The synthesis of these adamantylguanidine compounds, as taught by theSouth African patent, is by reaction of the corresponding amine:

with a reactant of the formula:

wherein Y represents a radical which can be split off. The aminecompound, in turn, is synthesized, in accordance with the teaching ofthe South African patent, by a three step reaction which is illustrated,where A is methylene and X is oxygen, by the following reactionsequence, in which Ad is used as an abbreviation for l-adamantyl:

Other synthesis routes, even more complex, are proposed for thesecompounds as Well as for those amine starting materials wherein X isimino or alkylimino.

Patented Nov. 10, 1970 ice SUMMARY OF THE INVENTION There has now beendiscovered a novel one-step process for the preparation of many of theadamantylamines useful as starting materials to synthesize theadamantylguanidine products of the South African patent above discussed.This process comprises the reaction, in the presence of an organictertiary amine, of a l-haloadamantane compound with an alkanolamine,yielding the corresponding (l-adamantyloxy)alkylamine directly. Cer tainof these (l-adamantyloxy)alkylamine compounds can be acetylated instandard procedures, yielding the corresponding N-acetyl derivatives.The products of the initial process, as well as the acetylatedderivatives thereof, are useful as central nervous system depressants.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directedto a process for the preparation of compounds of the formula Thisprocess comprises reacting, in the presence of an organic tertiaryamine, a l-halodamantane compound of the formula wherein each Rrepresents hydrogen or loweralkyl, the sum of the number of carbon atomsin all three R groups being not greater than 6; and X represents bromo,chloro, or iodo, with an alkanolarnine of the formula wherein Rrepresents hydrogen, methyl, or ethyl; R represents alkylene of from 1to 5, both inclusive, carbon atoms; and each of R and R takenseparately, independently represents hydrogen or loweralkyl of from 1 to4, both inclusive, carbon atoms, or R and R taken jointly with thenitrogen atom to which they are attached constitute pyrrolidine,piperidine, or morpholine. In this definition, hereinabove as throughoutthe present application, alkylene" is inclusive of both straight-chainalkylene as well as branched alkylene, and the term halo is employed todesignate bromo, chloro, and iodo, only.

In accordance with the present invention, representativel-haloadamantane compounds include:

l-chloroadamantane, l-bromoadamantane,1-bromo-3,5,7-trimethyladamantane, l-iodoadamantane,1-chloro-3,5,7-trimethyladamantane, 1-bromo-3-methyladamantane,1-bromo-3-ethyladamantane, 1-bromo-3-ethyl-5-methyladamantane,1-bromo-3,5 ,7 -triethyladamantane, 1-bromo-3,S-dimethyladamantane,1-bromo-3-isopropyladamantane, 1-chloro-3,S-dimethyladamantane, and1-bromo-3,S-di-n-propyladamantane;

and representative alkanolamine reactants include: 2-hydroxyethylamine,3-hydroxy-n-propylamine, 2-hydroxy-1,l-dimethylethylamine, 2-hydroxy-1,l,N,N-tetramethylethylamine, 1-(Z-hydroxyethyl)piperidine,

1- (Z-hydroxyethyl) morpholine, 1-(3-hydroxy-n-propyl)pyrrolidine,Z-hydroxy-n-propylamine, Z-hydroxy-N-methylethylamine,2hydroxy-N,N-diethylethylamine,

1- 2-hydroxyethyl) pyrrolidine, 4-hydroxy-n-butylamine,S-hydroxy-n-pentylamine, 2-hydroxy-N,N-di-sec-butylethylamine,Z-hydroxy-N-isopropylethylamine, 5-hydroXy-N,N-dimethyl-n-hexylamine,4-hydroxy-3-methyl-n-butylamine, 1-(Z-hydroxy-n-propyl)morpholine,Z-hydroxy-n-butylamine, and 6-hydroxy-n-hexylamine.

Preferred l-haloadamantane compounds are those wherein each R ishydrogen or methyl only.

The reaction of the l-haloadamantane compound and the alkanolamine iscarried out in the presence of an organic tertiary amine. The identityof such organic tertiary amine is not critical; liquid trialkylamines,pyridine, and alkyl-substituted pyridines, are suitable. Thus particulartertiary amines which are suitable to be employed in accordance with thepresent invention include triethylamine, tri-n-propylamine,tri-n-butylamine, pyridine, lutidine, especially 2,6-lutidine,a-collidine, fl-collidine, and 'y-collidine. For reactions carried outat the preferred reflux temperature, one of the foregoing amines whichis higher-boiling is required. Generally, triethylamine is the amine ofchoice for all reactions.

The reaction can be conducted in an inert liquid as a reaction medium.However, where one of the reactants or the organic tertiary amine is aliquid, an excess of such reactant or amine can be employed as a liquidreaction medium. Typically and preferably, triethylamine is employed asboth the tertiary amine and solvent for the reaction. The reaction goesforward under a wide range of temperatures, such as from 60 to 200 C.However, it is preferably conducted at reflux temperatures. The reactionconsumes the reactants and tertiary amine in amounts representingequimolecular proportions, but usage of an excess of the alkanolaminereactant is preferred. While the reaction goes forward immediately uponthe contacting of the reactants in the presence of the organic tertiaryamine, yielding some of the desired product almost at once, higheryields are obtained by permitting the reaction mixture to stand for aperiod of time in the reaction temperature range.

In carrying out the reaction, the reactants and organic tertiary amineare contacted with one another, with or without the use of an inertliquid reaction medium, and the reaction mixture is heated to thereaction temperature range and maintained for a period of time adequatefor the preparation of at least some of the desired product. Thereafter,the desired product is separated from the reaction mixture byconventional procedures, such as pouring into Water and extraction intoether. If desired, the product can be purified, also by conventionalprocedures, such as fractional distillation. oftentimes, separation andpurification are conveniently accomplished by making a salt of thedesired product and separating such salt by filtration and subsequentcrystallization.

Thus, in the foregoing method are prepared all the(1-adamantyloxy)alkylamine compounds of the formula:

:1. R R3 R obit-R -N 4 Those '(l-adamantyloxy)alkylamine compoundswherein either R or R represents hydrogen can be acetylated inconventional procedures to obtain the corresponding N- acety1-(l-adamantyloxy) alkylamine compounds:

wherein R represents the remaining R or R moiety, i.e., hydrogen orloweralkyl of from 1 to 4, both inclusive, carbon atoms. The acetylationcan be carried out in any conventional procedure; but not typically andconveniently, the acetylation is conducted by reacting the (1-adamantyloxy)alkylamine with acetic anhydride in pyridine. The reactionresults in the preparation of the desiredN-acetyl-(l-adamantyloxy)alkylamine compound, which can be separated byconventional procedures.

The following examples illustrate the present invention and will enablethose skilled in the art to practice the same.

Example 1 Preparation of 2-(l-adamantyloxy)-n-propylamine.-l-bromoadamantane (4.3 grams; 0.02 mole) and 2-hydroxy-n-propylamine(15.5 ml., 0.2 mole) were mixed together in triethylamine (5.6 ml.). Theresulting reaction mixture was heated to reflux temperature and refluxedfor 10 hours. At the end of this period of time, the reaction mixturewas poured onto ice-cold water and extracted with ether. The ether phasewas washed several times with water and then with dilute hydrochloricacid. The acid extract was Washed with ether and then basified withdilute sodium hydroxide. From the basified solution, the desired2-(l-adamantyloxy)-n-propylamine product was extracted into ether andthe extract washed with Water, dried over magnesium sulfate, andevaporated to separate the product as an oil. The product was distilled,

B.P., -101 C./0.2 mm. The product so obtained had a refractive index ofn 1.5103.

AnaZysis.Calc. (percent): C, 74.6; N, 6.7; H, 11.1. Found (percent): C,74.3; N, 6.9; H, 11.1.

Three grams of the product were dissolved in dry other (100 ml.). Thesolution was cooled to ice-cold temperature and dry hydrogen chloridegas passed into it. The reaction mixture was then evaporated to drynessunder vacuum, yielding 2-(l-adamantyloxy)-n-propylamine hydrochlorideproduct as a solid. After recrystallization from dioxane/ethanol thehydrochloride melted at 187- 9 C.

Analysis-Cale. (percent): C, 63.5; N, 5.7; H, 9.8. Found (percent): C,63.5; N, 5.9; H, 9.6.

Example 2 Preparation of 3-(l-adamantyloxy)-n-propylamine.-l-bromoadamantane (4.3 grams; 0.02 mole), 3-hydroxyn-propylamine (15.4ml.; 0.2 mole), and dry triethylamine (5.6 ml.) were mixed and refluxedfor about 10 hours. The reaction mixture was then worked up as describedin Example 1, yielding the desired 3-(1-adamantyloxy)-npropylamine as anoil. The oil was distilled, B.P., l00 102 C./0.2 mm. The refractiveindex was found to be "20D Analysis.Calc. (percent): C, 74.57; N, 6.69;H, 11.07. Found (percent): C, 74.29; 'N, 6.72; H, 11.08.

The hydrochloride melted at 155-7 C.

Analysi's.Calc. (percent): C, 63.53; N, 5.70; H, 9.85.

Found (percent): C, 63.37; N, 5.61; H, 10.17.

Example 3 Preparation of N-acetyl-2-(l-adamantyloxy)-n-propylamine.-2-(l-adamantyloxy)-n-propylamine (0.5 g.), prepared asdescribed hereinabove in Example 1, was mixed with pyridine (12 ml.) andacetic anhydride (5 ml.) and kept at room temperature for 72. hours. The

6 mixture was then poured onto ice water, and the organic Examples 23-26phase extracted into ether, washed with 5 percent aqueous bicarbonatesolution and water, and dried with magnesium other N'acfityl denvatlve?wh1c h be P P lf t removal f solvent and crystallization gave theaccordance with the present invention include those idendesiredN-acetyl-2.-( I-adamantyloxy) -n-propy1amine comtlfied herembelowi poundmeltmg at 104 6 5 N-acetyl-6-(l-adamantyloxy)-n-hexylamine Analysis-Cale(percent): C, 71.7; N, 5.6; H, 10.01.

Found (percent): 71.9; 9.84.N-acetyl-2-(l-adamantyloxy)-N-ethyl-n-butylamine N -acetyl-2-1-adamantyloxy)N-n-butylethylamine Examples 4-14 N-acety1-2H(l-adamantyloxy -.N-ispropyl-n-propylamine Other products are prepared inaccordance with the Those (1-adamantyloxy)alkylamine compoundswhereprocedures of Example 1, employing one mole of each in each of R, RR and R is hydrogen, and R is of the l-haloadamantane and triethylamineand a tenmethylene, are useful in the synthesis of the compounds foldmolar excess of the alkanolamine. The particular of South African Pat.65/4,102. However, all of the (1- starting materials, product, yield,and characterizing propadamantyloxy)alkylamine compounds as well astheir erty of the product are set forth in the following table. saltsand the corresponding N-acetyl compounds, are

Characterizing property of Product, Hydro- Percent B.P.,O. chloride,Example l-haloadamantane compound Alkanolamine Product yield mm. M.P.,C.

4. l-bromoadamantane 2-hydroxy-1,1,N,N-tetra-2-(1-adamantyloxy)-1,1,N,N-tetra- 120-2/0.3 160-3 methylethylamine.methylethylamin 2-hydroxyethylamine 2-(1-adamantyloxy)ethylamine 9089-90/0.1 206-8 Z-hvdroxy-N-methylethyla- 2-(1-adamanty1oxy)-N-methy1ethyl- 77 108-10/0.3 158-60 mine. amine. 2-hydroxy-N,N-diethyl-2-(1-adamantyloxy)-N,N-diethyl- 94 108-10/0. 2 152-3 ethylamine.ethylamine. 8 1-bromo-3,5,7-trimethyladamantane- 2-hydroxyethylamine2-(35g,7itrimethyl-l-adamaiityloxy)- 7 89 2 94-95 178-80 e yamine. 9l-bromoadamantane l-(l2ahydroxyethyl)-pyrro-1-(21-(1-adamanty1oxy)-ethyl)pyrrol- 87 195-8 1 me. 1 me. 10 .do1-(2-hydroxyethyl)-plperll-sizi-(l-adamantyloxy)-ethyl)piperl- 91132-4/0.1 246 e. no. 11 1-(2-hydroxyethyl)-morpho-1-(2-(l-adamantyloxy)-ethyl)mor- 90 225-7 pholine. pholine, 12 do4-hydroxy-n-butylamine- 4-(l-adamantyloxy)-n-butylamine 80 120/1. 0142-4 13 1-bromo-3,5,7-tri1nethyladamantane 4-hydroxy-n-butylam1ne...4-(3,g,7timethyl-l-adamantyloxy)- 00 2 74-76 281-3 nu y amine. 14l-bromoadamantane5-hydroxy-n-pentylaminefi-(l-adamantyloxy)-n-pentylam1iie. 72 158-60/5179-81 1 Decanoate. 2 Melting Point.-

Examples 15-19 useful as depressants for the central nervous system.Thus,

the compounds can be used in controlling hyper-excit- In otherrepresentative operations in accordance with ability in animals. Thecompounds can be administered in the present invention, otherl-haloadamantane compounds are reacted with other alkanolamines to givethe correy of Several methods, but generally the Oral method is spondingproducts in good yield. The reactants, organic pfefefable- The Compoundscan be used In 111106 at dosages tertiary amine, and product are setforth in the following 45 of up to 200 mg./kg. when administered orally,and at table: dosages of up to 400 mg. /kg. administered intraperitone-Organic tertiary Example l-Haloadamantane compound Alkanolamine amineProduct 15 l-chloroadamantane 2-hydroxy-n-buty1aminetri-n-butylamineZ-(I-adamantyloxy)-u-butylamine. 16 l-bromo-Ii-methyladarnautan2-hydroxysthylamine pyridine 2-(3-riiletlfyl-l-adamantyloxy)- e yamino.17 l-chloroadamantane 2-hydroxy-N,N-di-secbutylethylamine-..triethylamiiie 2-(1-adamantyloxy)-N,N-secbutylethylamine. 181-chloro-3,5-dimethyladamantane-. 3-hydroxy-n-pr0pylamine a-collidine3-(3,5-diinethyl-l-adamantyloxy)-npropy amine. 19l-bromo-3-isopropyladamantane 6-hydroxy-n-hexylamine 2,6-liiridine5-(3isopropyl-l-adamantyloxy)-nhexylaniine.

Examples 20-22 ally. Higher dosages can cause undesirable side effectsincluding toxic effects, and are therefore to be avoided.

Lesser amounts, of course, can be used and are often preferred in orderto achieve highly specific response.

The compounds cause desirable muscle relaxation, and

can therefore be employed as muscle relaxants. In representativeprocedures, groups of mice, two mice per group, were employed in theevaluation of various comldentifying pounds of the present invention.Each group was ad- Name of compound characteristic ministered one of thecandidate compounds and all groups were thereafter observed inaccordance with standardized In yet other operations, representativecompounds prepared in accordance with the process of the presentinvention were thereafter acetylated in accordance with the proceduresof Example 3. The compounds thus obtained, and their identifyingcharacteristics, are listed in the following table.

N-acetyl-2-(l-adamantyloxy)ethylamine -8 0.N-acetyl-2-(l-adamantyloxy)-N-methylethylamine- 150 0. 0.4 testprocedures for the changed response of the mice in mm.N-acety1-2-(3,5,7-trimethyl-1-adamantyloxy) 3 tests for grasping loss,abdominal tone loss, foreleg weakctli lamine. ness, and hindlcgweakness, indicators of muscle relaxalMelting Point, tion. In thesetests, each of the compounds listed below showed muscle relaxation, atthe dosage set forth and in the mode of administration identified Inthis following table, ip is employed as an abbreviation for the termintraperitoneal.

Mode of adminis- Dosage (in Name of compound tration rug/kg.)

1-(2-(1-adarnantyloxy) ethyl) -pyrro1idine Oral 100 hydrochloride. 1-(2-(1-adamantyloxy) ethyl) -n1orpho1ine i.p 100 hydrochloride4-(l-adamantyloxy)-n-butyl-amine i.p 50

hydrochloride. N-acetyl-Z-(3,5,7-trimethy1-1-adamantyloxy) i.p 400ethylamine. 5-(1-adamantyloxy) -n-penty1-amine i.p 100 hydrochlroide.

We claim: 1. A compound of the formula:

1 e 1} 2 R O-CH-R -N fi-Cli R 0 wherein each R represents hydrogen orloweralkyl, the sum of the number of carbon atoms in all three R groupsbeing not greater than 6; R represents hydrogen, methyl, or ethyl; Rrepresents alkylene of from 1 to 5 both inclusive, carbon atoms; and Rrepresents hydrogen or loweralkyl or from 1 to 4, both inclusive, carbonatoms.

2. The compound of claim 1 which is N-acetyl-Z-(ladamantyloxy)ethylamine.

3. The compound of claim 1 which is N-acetyl-Z-(lad amantyloxy-n-propylamine.

4. The compound of claim 1 which is N-acetyl-2-(3,5,7-trimethyll-adamantyloxy) ethylamine.

References Cited UNITED STATES PATENTS 3,270,036 8/1966 Bernstein et a1.260-343.7

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

